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An Integrated National System for Addressing Foreign Animal Diseases and Zoonotic Diseases

US federal agencies have a responsibility for and a vital role in the prevention, detection, and control of foreign animal diseases (FADs) and zoonotic diseases that have the potential for broad health and socioeconomic effects. Historically, the US Department of Agriculture (USDA) has addressed disease threats to the agricultural animal industries that may occur as a result of introduction of an FAD, and confronting the potential human health effects of zoonotic diseases has been the responsibility of the Department of Health and Human Services. Although the historical mandates of those agencies have not changed, the disease threats have. The threat of bioterrorism, heightened after the events of September 11, 2001; the later creation of the Department of Homeland Security (DHS); and advances in biotechnology that have increased the risk of purposeful or inadvertent modifications of microorganisms that could increase virulence, expand host range, or enhance transmissibility (Berns et al., 2012; Enserink and Cohen, 2012) have drawn the world’s attention to the threat of disease outbreaks. Our growing global interconnectivity; the growing global population; the demand for food, particularly animal-based protein; and increasing contact with wild ecosystems through land development make it likely that emerging and re-emerging pathogens will continue to occur and spread at an even greater rate. Scientists predict that two to four new pathogens will emerge each year and that RNA viruses, especially those at the human-animal interface, will present the greatest threat (Brownlie et al., 2006). The factors that could create “the perfect microbial storm”, as described by the Institute of Medicine (IOM, 2003), are still in place and intensifying, and this suggests that the risk of disease incursion continues to increase and that the implications are even more profound. The impact of those factors has been felt on local to global levels, and has resulted in policy changes in disease reporting by such international agencies as the World Health Organization (WHO) through the codification of the



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3 An Integrated National System for Addressing Foreign Animal Diseases and Zoonotic Diseases US federal agencies have a responsibility for and a vital role in the preven- tion, detection, and control of foreign animal diseases (FADs) and zoonotic dis- eases that have the potential for broad health and socioeconomic effects. His- torically, the US Department of Agriculture (USDA) has addressed disease threats to the agricultural animal industries that may occur as a result of intro- duction of an FAD, and confronting the potential human health effects of zoono- tic diseases has been the responsibility of the Department of Health and Human Services. Although the historical mandates of those agencies have not changed, the disease threats have. The threat of bioterrorism, heightened after the events of September 11, 2001; the later creation of the Department of Homeland Secu- rity (DHS); and advances in biotechnology that have increased the risk of pur- poseful or inadvertent modifications of microorganisms that could increase viru- lence, expand host range, or enhance transmissibility (Berns et al., 2012; Enserink and Cohen, 2012) have drawn the world’s attention to the threat of disease outbreaks. Our growing global interconnectivity; the growing global population; the demand for food, particularly animal-based protein; and increas- ing contact with wild ecosystems through land development make it likely that emerging and re-emerging pathogens will continue to occur and spread at an even greater rate. Scientists predict that two to four new pathogens will emerge each year and that RNA viruses, especially those at the human-animal interface, will present the greatest threat (Brownlie et al., 2006). The factors that could create “the perfect microbial storm”, as described by the Institute of Medicine (IOM, 2003), are still in place and intensifying, and this suggests that the risk of disease incursion continues to increase and that the implications are even more profound. The impact of those factors has been felt on local to global levels, and has resulted in policy changes in disease reporting by such international agen- cies as the World Health Organization (WHO) through the codification of the 35

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36 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE International Health Regulations in 2005 (WHO, 2007) and the revised list of notifiable diseases (see Table 2-1 in Chapter 2) and requirements for notification of emerging diseases by the World Organisation for Animal Health (OIE, 2010). Commensurate with those changes is an expectation that WHO and OIE mem- ber countries will have a reliable infrastructure for disease surveillance and re- sponse (Fidler, 2005; Baker and Fidler, 2006). As noted in Chapter 2, a number of previous National Research Council (NRC) and IOM studies have addressed current threats to our nation’s health and welfare, including both FADs and zoonotic diseases (IOM, 2003). A recent IOM and NRC report, Sustaining Global Surveillance and Response to Emerg- ing Zoonotic Diseases (2009), is of particular relevance and recommended sev- eral actions to strengthen the global capacity for addressing disease threats. The recommendations included improved use of information technology (Recom- mendation 1-2), a strengthened global laboratory network (Recommendation 1- 3), and expanded human-resource capacity (Recommendation 1-4) to support disease surveillance and response (IOM and NRC, 2009). The recommendations for a global system apply equally to the framework for animal-disease surveil- lance and response within the United States, whether for zoonotic diseases or FADs. Protecting US animal agriculture requires a well-integrated system that spans authorities, geography, and many programs and activities. The idea that a chain is only as strong as its weakest link applies to the complex systems needed to protect animal agriculture from the incursion of serious diseases and to ad- dress a riskier world. THE ROLE OF A NATIONAL LABORATORY FACILITY IN AN INTEGRATED SYSTEM Critical Core Functions The committee considered its task in the context of an integrated system in the United States for addressing FAD and zoonotic disease threats and the role of a national biocontainment laboratory in such a system. The ideal system would capture and integrate the substantial human and physical assets distrib- uted throughout the nation to optimally address the threat of FADs and zoonotic diseases. It would include surveillance and detection, diagnostics, and disease response and recovery and would have research and development and training of the workforce as critical core elements to support each of these functional arms (see Figure 3-1). These elements would provide the capabilities needed to sup- port multiple disease-control strategies, the choice of which is dependent on many factors such the likelihood of introduction to the United States, disease spread rates, and cost and effectiveness of control. A robust laboratory infra- structure underlies all those components. A national role in the coordination of the system is essential, and a federal laboratory or network of laboratories would be the cornerstone of the system. The ideal system would reach beyond our bor- ders to tap the expertise and resources of the global infectious-disease surveil-

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AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 37 lance, diagnostic, and research communities. Recognizing the threat posed by zoonotic diseases and the known and potential roles of animals in maintaining and transmitting infectious agents, the ideal system would capture both human- and animal-health expertise and laboratory infrastructure to achieve the common goals of disease recognition and response. T rained Workforce Integrated System for Disease Threats Diagnostic Laboratory Network FIGURE 3-1 Components of an integrated national system for addressing foreign animal disease and zoonotic disease threats. Laboratory infrastructure underlies all components. Surveillance At the heart of early recognition of a newly introduced disease, whether its occurrence is intentional or natural, is the ability to gather and access data from the field. Technology for capturing the billions of bits of information flowing through electronic channels every day can help to detect unusual events in real time, but it is unlikely that a technology-based approach to data acquisition will ever be the sole or most accurate means by which we can recognize a disease occurrence in the United States. Human resources and a trained workforce are vital to early recognition and verification of an emerging disease event. It is es- sential to ensure that trained personnel, both professional and lay, are well versed in the manifestations of known diseases in animals and humans and at- tuned to the variations in disease expression that can indicate a newly emerging disease event. The various clinical signs and pathological changes caused by FAD and zoonotic disease agents can be demonstrated effectively with experi- mental inoculation of animals, and many FAD and zoonotic disease agents re- quire animal biosafety level 3 (ABSL-3), biosafety level 3 agriculture (BSL- 3Ag), or ABSL-4 containment for live-animal work; so training of the work- force in early detection is an essential function that should be provided by a cen-

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38 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE tral laboratory that has appropriate biocontainment (see Box 3-1 for the descrip- tion of biosafety levels). The committee agreed that the strategic use of video imaging, plastination (fixation, dehydration, impregnation, and hardening of tissues), and other technological means to capture and broadly disseminate train- ing materials through electronic media, and engagement of the workforce in disease-control campaigns in regions that are endemic for animal diseases or that experience outbreaks of diseases foreign to the United States could reduce the need for hands-on training with experimentally infected animals and thereby reduce the need for training space in the proposed NBAF. BOX 3-1 Laboratory Biosafety Levels and Types of Pathogens Handled at Each Level as defined in The Biosafety in Microbiological and Biomedical Laboratories, 5th Edition Biosafety Level 1 (BSL-1): Biosafety Level 1 is suitable for work involving well-characterized agents not known to consistently cause disease in immunocompe- tent adult humans, and present minimal potential hazard to laboratory personnel and the environment. Biosafety Level 2 (BSL-2): Biosafety Level 2 builds upon BSL-1. BSL-2 is suitable for work involving agents that pose moderate hazards to personnel and the environment. It differs from BSL-1 in that: 1) laboratory personnel have specific training in handling pathogenic agents and are supervised by scientists competent in handling infectious agents and associated procedures; 2) access to the laboratory is restricted when work is being conducted; and 3) all procedures in which infectious aerosols or splashes may be created are conducted in biosafety cabinets or other physical containment equipment. Biosafety Level 3 (BSL-3): Biosafety Level 3 is applicable to clinical, diagnos- tic, teaching, research, or production facilities where work is performed with indige- nous or exotic agents that may cause serious or potentially lethal disease through the inhalation route of exposure. Animal Biosafety Level 3 (ABSL-3): Animal Biosafety Level 3 involves prac- tices suitable for work with laboratory animals infected with indigenous or exotic agents, agents that present a potential for aerosol transmission, and agents causing se- rious or potentially lethal disease. Biosafety Level 3 Enhanced (BSL-3E): Situations may arise for which en- hancements to BSL-3 practices and equipment are required; for example, when a BSL-3 laboratory performs diagnostic testing on specimens from patients with hem- orrhagic fevers thought to be due to dengue or yellow fever viruses. When the origin of these specimens is Africa, the Middle East, or South America, such specimens might contain etiologic agents, such as arenaviruses, filoviruses, or other viruses that are usually manipulated in a BSL-4 laboratory. Examples of enhancements to BSL-3 laboratories might include: 1) enhanced respiratory protection of personnel against aerosols; 2) high-efficiency particulate air filtration of dedicated exhaust air from the laboratory; and 3) personal body shower. (Continued)

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AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 39 Box 3-1 Continued Biosafety Level 3 Agriculture (BSL-3Ag): In agriculture, special biocontain- ment features are required for certain types of research involving high consequence livestock pathogens in animal species or other research where the room provides the primary containment. To support such research, the US Department of Agriculture has developed a special facility designed, constructed and operated at a unique ani- mal containment level called BSL-3Ag. Using the containment features of the stan- dard ABSL-3 facility as a starting point, BSL-3Ag facilities are specifically designed to protect the environment by including almost all of the features ordinarily used for BSL-4 facilities as enhancements. Biosafety Level 4 (BSL-4)1: Biosafety Level 4 is required for work with dan- gerous and exotic agents that pose a high individual risk of aerosol-transmitted labo- ratory infections and life-threatening disease that is frequently fatal, for which there are no vaccines or treatments, or a related agent with unknown risk of transmission. Agents with a close or identical antigenic relationship to agents requiring BSL-4 con- tainment must be handled at this level until sufficient data are obtained either to con- firm continued work at this level, or re-designate the level. SOURCE: CDC (2009). Training at a national facility can be supplemented, for example, with  USDA Animal and Plant Health Inspection Service (APHIS) online re- sources.2  The online FAD information and Emerging and Exotic Diseases of Animals (EEDA) course provided by the Center for Food Security and Public Health at Iowa State University.3  The Foreign Animal Disease Training Course at Colorado State Uni- versity.4  The Foreign Animal, Emerging Diseases course at the University of Tennessee College of Veterinary Medicine.5 1 The designation “ABSL-4 large animal” is a terminology used by DHS to specify ar- eas where biosafety level 4 research in large animals is conducted, but this term has not been codified by the BMBL. 2 URL: http://www.aphis.usda.gov/emergency_response/NAHEM_training/index_nahem.s html (accessed June 1, 2012). 3 URL: http://www.cfsph.iastate.edu/EEDA-Course/ (accessed June 1, 2012). The EEDA Web-based course was developed in 2000-2002 by Iowa State University, the University of Georgia, the University of California, Davis, and USDA. It has been used since 2002 in US veterinary schools to raise awareness of foreign, emerging, and exotic animal dis- eases and the appropriate responses if an unusual disease is suspected. The EEDA book is provided to all students at veterinary colleges and schools in the United States through funding from APHIS. 4 URL: http://www.cvmbs.colostate.edu/aphi/ (accessed June 5, 2012).

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40 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE  Continuing-education courses, such as Response to Emergency Animal Diseases in Wildlife,6 and other online and digital media sources of FAD information (such as a CD on FADs provided by the National Center for Animal Health Emergency Management).7  Core or elective courses in FADs that are required to be in the curricula of the 28 accredited colleges and schools of veterinary medicine in North America.  Specialized courses in FAD recognition, such as the Smith-Kilborne FAD course offered at the Cornell University College of Veterinary Medicine and Plum Island Animal Disease Center (PIADC).8 Box 3-2 summarizes current FAD courses offered at PIADC. BOX 3-2 Training Courses Offered at the Plum Island Animal Disease Center Foreign Animal Disease Diagnostics Course The regular Foreign Animal Disease Diagnostics (FADD) course is intended to train veterinarians employed by federal agencies (mostly USDA-APHIS Veterinary Services), by states, and by the military (primarily the Army Veterinary Corps). The FADD training course is provided three times a year with a maximum participation of 30 veterinarians each time. Today, federal, state, and military veterinarians take the same course (the military Transboundary Animal Diseases (TAD) course was separate for several years). The course includes live experimental animal demonstrations of 11 important livestock diseases (such as foot-and-mouth disease, classical swine fever, exotic Newcastle disease, and highly pathogenic avian influenza) and lectures on 23 diseases of livestock and poultry species. It also covers lectures and demonstrations on the use of personal protective equipment; on-farm disease investigation; collection, packaging, and mailing of diagnostic samples; and administrative procedures related to disease investigation, reporting, and emergency response. Veterinary Laboratory Diagnostician Course A separate 1-week course is offered to faculty and residents of US veterinary col- leges and schools each year. It follows the same format as the FADD course. Partici- pants do not spend much time in USDA-APHIS administrative training, and they do not become FAD diagnosticians. (Continued) 5 URL: http://www.veterinarypracticenews.com/vet-breaking-news/foreign-animal-em erging-disease-course.aspx (accessed June 6, 2012). 6 URL: http://www.aphis.usda.gov/animal_health/prof_development/ (accessed June 4, 2012). 7 Jon Zack, USDA-APHIS, pers. comm., June 1, 2012. 8 URL: http://www.aphis.usda.gov/animal_health/prof_development/smith_kilborne.shtml (accessed May 31, 2012).

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AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 41 BOX 3-2 Continued International Transboundary Animal Diseases Course The International Transboundary Animal Disease (ITAD) course is organized and funded through USDA-APHIS International Services (in contrast with the above courses, which are organized and funded through USDA-APHIS Veterinary Services). The course has been given 11 times, once almost every year, with up to 30 international veterinarians each time. It has been delivered completely in Spanish six times. Partici- pants are selected by veterinary and agricultural attachés from among government or academic veterinarians around the world. As in the case of the FADD and the Veterinary Laboratory Diagnostician courses, there is no fee to attend this course; the participants’ sponsoring institutions pay for associated travel, lodging, and meals. The ITAD course follows the same schedule and animal demonstrations as the regular FADD course, ex- cept that participants do not spend time on USDA-APHIS administrative policies and procedures; instead, they are exposed to discussion on international trade, epidemiology, and emergency response. Smith-Kilborne Foreign Animal Disease Course This course in the current format has been delivered for 10 years and includes one veterinary student (after completion of their second year) from each of the 28 US col- leges and two international veterinary students (from Canada or Mexico). The Smith- Kilborne program is designed to acquaint veterinary students with various FADs that potentially threaten our domestic animal population. The course includes classroom presentations for 3 days at Cornell University College of Veterinary Medicine on dis- eases and their implications and 2 days of laboratory experience at the PIADC, where participants observe foot-and-mouth disease, African horse sickness, highly pathogenic avian influenza, and exotic Newcastle disease. The PIADC portion of the course coin- cides with the first week of a regular FADD course, and experimentally infected animals are shared by the two courses. Students practice necropsies on poultry only. After the course, students are expected to share their new knowledge by giving seminars at their colleges. Apart from the need to maintain a trained and ready workforce and a poten- tial research and development requirement to support this component, field- based surveillance itself does not require high-biocontainment (BSL-3 and BSL- 4) space, although case or outbreak investigations of zoonoses may require use of appropriate personal protective equipment (PPE). Diagnostics Historically, the National Veterinary Services Laboratories (NVSL) at Ames, Iowa have provided support for diagnosis of endemic “program dis- eases”9 in the United States by qualified and approved nonfederal laboratories. Training programs for laboratory personnel, proficiency testing, and reference 9 Program diseases are those designated as “necessary to bring under control or eradi- cate from the United States” (APHIS, 2012).

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42 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE reagents have been valuable contributions to state laboratories’ ability to per- form diagnostic testing for control programs targeting such endemic diseases as brucellosis, pseudorabies, tuberculosis, and equine infectious anemia. The role of the NVSL Foreign Animal Disease Diagnostic Laboratory (FADDL), which is co-located with USDA-ARS and DHS at the PIADC, has been more limited in that it has focused on FADs, for which nonfederal laboratories were not allowed to perform diagnostic testing. The development of the National Animal Health Laboratory Network (NAHLN) in 2002 and associated changes in policy (Memorandum 580.4)10 now allow state laboratories to conduct diagnostic test- ing for FADs. Box 3-3 provides an overview of the NAHLN from its inception to the present. The NAHLN is an excellent example of an integrated system that was cre- ated to address the nation’s needs, in this case for diagnostic support for early detection, response to an outbreak, and recovery. With the implementation of the NAHLN, the NVSL laboratories at the National Centers for Animal Health (NCAH) in Ames, Iowa, and FADDL at Plum Island now play a vital and irre- placeable role in supporting testing for FADs in approved NAHLN laboratories. Initial test validation (including analytical assessment with samples collected from experimentally infected animals, diagnostic sensitivity, and specificity determination with samples obtained from outbreaks in endemic areas outside the United States, which can be handled only at PIADC and NCAH), reference- reagent production, and proficiency testing are all examples of the critical core functions best managed by a federal laboratory in support of diagnostic testing on a nationwide basis in qualified laboratories. Continued assessment of vali- dated assays against newly arising variants obtained from outbreaks outside the United States also requires adequate biocontainment. For foot-and-mouth dis- ease, this is performed in a federal facility approved for handling of foot-and- mouth disease virus (FMDv) . Finally, the role of NVSL in confirmatory diagnosis of the index case of an FAD cannot be overvalued. Because of the inevitable effects on lives and liveli- hoods, the index case of a new disease in the United States must be officially reported by a federal agency. The current role of state NAHLN laboratories in the diagnosis of an index case of a potential FAD is to obtain a test result that is actionable but presumptive; appropriate samples are also sent to NVSL, Ames or Plum Island for confirmation. Assays such as cell culture used for confirmatory diagnosis result in amplification of a virus that may be highly contagious and requires a modern, high-biocontainment laboratory environment like that pro- posed for the NBAF. The ability to culture live FAD pathogens like FMDv for characterization and reference is a critical core function of a national biocon- tainment laboratory. 10 URL: http://www.aphis.usda.gov/animal_health/lab_info_services/downloads/VSMe mo580_4.pdf (accessed May 31, 2012).

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AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 43 BOX 3-3 The National Animal Health Laboratory Network The National Animal Health Laboratory Network (NAHLN), launched in 2002, is a cooperative effort of the US Department of Agriculture (USDA) Animal and Plant Health Inspection Service, the USDA National Institute of Food and Agricul- ture, and the American Association of Veterinary Laboratory Diagnosticians (AAVLD). The mission of the NAHLN is to provide accessible, timely, accurate, and consistent animal disease diagnostic services nationwide that meet the epidemiologi- cal and disease reporting needs of the country. The NAHLN also maintains the capac- ity and capability to provide laboratory services in the event of an FAD or emerging disease event in the country. The NAHLN focuses on diseases of livestock, but it also responds to disease events in nonlivestock species. The NAHLN has contributed to several surveillance activities and control strategies of national interest. The NAHLN laboratories are the first line of early detection of transboundary diseases and serious zoonotic diseases introduced into the United States. The origins of the NAHLN are in the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 and Homeland Security Presidential Direc- tive 9 (HSPD-9), both of which called on USDA to establish surveillance systems for animal diseases that would mitigate threats to the nation’s agricultural sector. The USDA Safeguarding Review (NASDARF, 2001) identified the need for a network that would coordinate laboratory capacity at the federal level with the exten- sive infrastructure of the state and university animal disease diagnostic laboratories. Cooperative agreements were awarded by USDA in May 2002 to 12 state and univer- sity diagnostic laboratories for a 2-year period. The NAHLN has grown to 58 labora- tories (53 state and five federal) in 40 states (see Figure 3-2), and the capability and capacity of the nation’s animal-disease surveillance program have grown with it. At the federal level, USDA’s National Veterinary Services Laboratory (NVSL) laboratory units in Ames, Iowa, and Plum Island, New York (Foreign Animal Disease Diagnostic Laboratory [FADDL]), serve as the national reference and confirmatory laboratory for veterinary diagnostics, and it coordinates the training, proficiency test- ing, assistance, and prototypes for diagnostic tests that are used in the state NAHLN laboratories. One component of NVSL’s contribution to the NAHLN is a “train the trainer” program that has increased the number of personnel in NAHLN laboratories who can perform tests for the diagnosis of FADs. The program, offered at FADDL and NVSL, Ames is an example of the successful collaboration between the NVSL and NAHLN laboratories that has resulted in a national network of laboratory person- nel who are trained to perform tests for FADs—a resource that did not exist before the NAHLN. The state and university animal-disease diagnostic laboratories in the NAHLN perform routine diagnostic tests for endemic animal diseases, and they have received specific approval to perform tests for FADs as a part of the national surveillance strategy. A current example of the NAHLN’s value is the diagnosis of the fourth US case of bovine spongiform encephalopathy (BSE), reported by USDA on April 24, 2012. A sample collected from a dairy cow was submitted to the California Animal Health and Food Safety (CAHFS) laboratory at the University of California at Davis, (Continued)

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44 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE BOX 3-3 Continued an NAHLN laboratory that performs BSE testing through a contractual agreement with USDA. When the CAHFS laboratory determined that the sample was positive, suspect, or inconclusive for BSE, it was sent to the NVSL for confirmation. That procedure is rou- tine and conforms with the established protocol outlined in a Veterinary Services memo- randum (VS Memorandum 580.4). Thousands of BSE tests have been performed in NAHLN laboratories in support of USDA’s BSE surveillance strategy. Similar testing agreements for a wide array of animal diseases—including foot-and-mouth disease, clas- sical swine fever, avian influenza, exotic Newcastle disease, chronic wasting disease and scrapie, swine influenza, pseudorabies, and vesicular stomatitis—have been established with NAHLN laboratories nationwide. The NAHLN effectively demonstrates the value of collaboration between the federal government and state and university animal-disease diagnostic laboratories and may serve as a template for a new relationship among the Department of Homeland Security, USDA, and the NAHLN. Such a new collaboration could accomplish some of the tasks of the proposed National Bio- and Agro-Defense Facility (NBAF) by using infrastructure that already exists in the state and university veterinary diagnostic network, including facilities, professional expertise, and support. FIGURE 3-2 National Animal Health Laboratory Network. SOURCE: USDA-APHIS (2012). SOURCE: USDA-APHIS (2012).

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AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 45 Outbreak Response If the United States identifies a known FAD or a newly emergent disease within its borders, a rapid, comprehensive response is necessary. The type of response will depend on the disease and on whether it is known or newly identi- fied. The historical approach for control of an FAD outbreak has been to quaran- tine infected premises with diagnostic screening in surrounding zones followed by additional quarantine and diagnostic screening focused on new infected premises with slaughter of infected animals. That approach requires that new cases be rapidly identified with diagnostic assays that have a high level of diag- nostic sensitivity and the capability of being performed in a high-throughput manner, particularly in the case of rapidly spreading diseases, such as foot-and- mouth disease. Technological advances in the last few decades have led to the development of direct pathogen identification assays that have very high sensi- tivity, that target and amplify nucleic acids, and that have the capability of high throughput. The NAHLN has successfully deployed well-validated real-time polymerase chain reaction (PCR) assays for detection of foot-and-mouth dis- ease, avian influenza, pandemic H1N1 influenza, classical swine fever, African swine fever, and rinderpest. That would not have been possible without the sup- port of a federal laboratory: initial validation of the assays was conducted at PIADC, where samples from experimentally inoculated animals were vital for early analytical sensitivity testing. Continuing support for reference reagents, proficiency testing, and ensuring that reagents are available in required quanti- ties to respond to a disease outbreak is fundamental to being prepared and re- sponsive during a real event. It is a function that can best be performed by a fed- erally supported program that includes appropriate laboratory biocontainment. The United States is increasingly incorporating vaccination into outbreak- response plans for FADs. This scientifically sound and justifiable approach is expected by a populace that increasingly respects the value and welfare of agri- cultural animals beyond their place in the food chain. Vaccines would probably be used strategically in “ring vaccination” to minimize the number of animals that would need to be killed to control an outbreak. Vaccine development has been going on at PIADC for many years, but as a result of the change in out- break response and the acceptance of regionalization and compartmentalization by OIE, a higher priority has been attached to vaccine development where gaps exist, and the goal is to develop vaccines that allow differentiation of infected from vaccinated animals (“DIVA” vaccines) and diagnostics. Research on vac- cine development for FAD agents requires the ability to grow and manipulate an agent, which in turn requires biocontainment at BSL-3, BSL-3Ag, BSL-3E lev- els, and—for agents such as Hendra and Nipah viruses, hemorrhagic fever vi- ruses, and some arboviruses—BSL-4 level. Equivalent ABSL containment is required for live-animal work. It is important to note that all the viral agents that require BSL-4 containment are zoonotic; that is, none of the livestock-specific FADs require BSL-4 laboratory containment. Nevertheless, a disease outbreak of a zoonotic virus that requires BSL-4 containment would require appropriate

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56 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE The National Institute of Allergy and Infectious Diseases, which is part of NIH, supports 11 university-based laboratories designated as Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases (RCEs). The RCEs conduct research on NIH priority pathogens, some of which are agents of FADs and zoonotic diseases that appear on the OIE lists of animal diseases and top animal disease threats in the United States (see Tables 2-1 and 2-3 in Chapter 2). Most BSL-4 facilities have a common design that couples dedicated in vitro laboratories with adjacent animal rooms, almost always augmented by dedicated rooms for necropsy or animal manipulation. Animal rooms are usually about 200-350 ft2 each and are designed to hold rodents, rabbits, or other small ani- mals in racks; each animal room typically can hold two or more racks. The rooms may also hold nonhuman primates, which are often housed in racks of four individual cages (two up, two down), and a single animal room typically can hold 16 or more nonhuman primates. Widely available modern isolation units isolate individual cages and limit air mixing between cages of many smaller laboratory animals, so it is possible to undertake concurrent experiments with different pathogens by using separate animal cages in the same room “Biobubbles” or “biorooms” can serve the same purpose for nonhuman primates but are less commonly used. Animal rooms used to house nonhuman primates are usually equipped with floor or trench drains with strainers to separate solid waste. They discharge to a central set of reservoirs where waste is sterilized be- fore being discharged into the local sewage system. Floor drains may or may not be in place for animal rooms designed to hold rodents or other small animals. All solid waste and animal carcasses are sterilized (autoclaved) before leav- ing the biocontainment laboratory and then usually incinerated. Few of these facilities have large “digesters” capable of processing experimentally infected larger animals. Movement of laboratory animals into biocontainment laborato- ries often involves the use of elevators and passage through open hallways and loading docks. Waste, animal cages, and bedding are sterilized in double-door autoclaves as the material leaves the laboratory. Equipment and other imple- ments can also be decontaminated in an air lock in which a gas (formaldehyde) or vapor (hydrogen peroxide) is used to fumigate the items. Materials that have been autoclaved or fumigated are then usually cleaned and prepared for reuse at a central facility, often in the laboratory complex. The handling of agriculturally important animals in existing BSL-4 facilities is challenging but not impossible, although no such facility in the United States is designated as ABSL-4 for large animals. Some facilities are exploring the use of miniature goats or pigs for experimental infection with agriculturally impor- tant BSL-4 pathogens, such as Crimean-Congo hemorrhagic fever, Nipah, and Hendra viruses. There are many challenges in conducting such experiments,

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AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 57 including movement of animals from the supplier into the biocontainment labo- ratory, animal husbandry and waste management during experimentation, ma- nipulation of large animals in the BSL-4 environment, necropsy procedures, and decontamination of animal carcasses after experimental infection. Those chal- lenges are more fully discussed below. Choice of Animals Miniature goats, pigs, young lambs, and perhaps miniature horses could be used for experimental infections in existing BSL-4 facilities in the United States. Larger animals, such as horses and cattle, would present major hurdles and are probably not practical apart from true emergency conditions. The number of individual animals able to be tested at a given time will be small, and this could make it difficult to demonstrate statistically significant results. Special equip- ment for safe handling of any large animals would have to be procured and in- stalled. Delivery of Animals Many existing BSL-4 laboratories are not on the ground level of the build- ings that house them. Therefore, animals would need to be moved from a trans- port vehicle to a biocontainment facility by using existing delivery docks, hall- ways, and elevators that were not designed for movement of large animals. That problem could be overcome by using crates or other containers for some species and restricting access while animals are being moved. Animal Husbandry Animal husbandry is likely to be one of the most challenging aspects of the use of domestic animals in existing biocontainment facilities. Special flooring will be needed to allow efficient waste removal and to provide adequate footing for and protection of hoofed animals. Individual corrals can be purchased and installed, or animals can be group-housed in a designated portion of an animal room. Special arrangements will be required for feed and water. Monitoring Animals Individual animals can be monitored for vital signs, such as body tempera- ture, with implanted sensors and telemetry. However, direct handling of individ- ual animals for inoculation or to obtain periodic blood samples or other speci- mens would require the installation of appropriate constraint devices and their use by trained personnel to facilitate the safe handling of the animals during such manipulations.

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58 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE Necropsy and Carcass Disposal Most necropsy facilities that are now in place are designed to handle labora- tory animals that are the size of nonhuman primates or smaller. Special adapta- tions might be required to process larger animals, and preparation of carcasses to ensure sterilization on completion of studies will be difficult. Disposal of larger animals after sterilization would require specialized large incinerators that may not be locally available. Institutional Oversight All animal experimentation must be reviewed and approved by an institu- tional animal care and use committee, and the handling of dangerous pathogens must be cleared by an institutional biosafety committee. Those committees en- sure that work to be done meets all existing national standards and that it can be accomplished safely and securely. In most instances, the institutions will not have had experience in handling large livestock species, particularly those being experimentally infected with infectious agents. Convincing the committees that domestic animals can be manipulated safely and securely under humane condi- tions in facilities adapted to accommodate large animals will require careful planning, effective leadership, and a strong partnership between the scientific investigators and the laboratory animal resources team. International Resources BSL-4 laboratories outside the United States that have the capacity to han- dle large animals are shown in Table 3-2. Each facility has the ability to handle large domestic animals and some of these laboratories have experience working with agents that are not currently in the United States but are of research interest and could be newly introduced into the country (for example, Hendra and Nipah viruses at the Australian Animal Health Laboratory in Geelong). Depending on the situation when a request is made, they may be willing to collaborate with US scientists to investigate pathogens that require BSL-4 containment. Their pri- mary responsibility is, of course, to their own national governments and domes- tic needs. National and international resources and biocontainment infrastructure for addressing the threat of FADs and zoonotic diseases have expanded substan- tially since 2001. A discussion of some of the requirements and challenges asso- ciated with the design and construction of international high-containment labo- ratories may be found in the report entitled Biosecurity Challenges of the Global Expansion of High-Containment Biological Laboratories (NAS and NRC, 2012). Can components of the ideal system for countering disease threats use these existing resources effectively? The answer is a cautious yes. However, the chal-

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AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 59 lenges in using the highest level of biocontainment space (ABSL-4), particularly for large-animal research and diagnostic development, are not insignificant. Adaptability and Flexibility for the Future Technology Diagnostics, detection, vaccine development, and therapeutics are primary research necessities to maintain US agricultural strength. The scientific and technological needs of the diagnostic and response capability of the United States were outlined in the 2003 National Research Council report Countering Agricultural Bioterrorism: “There are needs and opportunities for aggressive research in both science and technology to improve our ability to prevent, detect, respond to and re- cover from biological attacks on agricultural plants and animals. The scien- tific knowledge and the technological developments for protecting plants and animals against naturally occurring or accidentally introduced pests and pathogens constitute a starting point for these efforts—but only a starting point—and there is much more to be done” (p. 67, NRC, 2003). Knowledge of naturally occurring agents is itself limited, and the landscape is complicated if one considers intentional introduction of existing or novel “synthetic” threat agents. Identification and characterization of existing patho- gens continue to accumulate at rates that are increasing dramatically as a result of new technologies, such as next-generation sequencing. In general, diagnostic tests are moving away from antibody-based, single-pathogen laboratory assays toward nucleic acid-based, multiple-pathogen point-of-care tests. None have yet been considered fit for the purpose of diagnosing FADs of livestock (whose prevalence is virtually zero). However, a survey of recent developments in bio- technology suggests that new, effective methods for diagnosing and tracking human diseases are available or on the near horizon, application to companion- animal diseases has already occurred, and further development for diseases of livestock will follow. Nanotechnology and microfluidics have contributed to the burgeoning of detection technologies. For example, several advances in nucleic acid-based detection devices will allow diagnosis of known infections—even of infection with BSL-3 organisms—in the field or in the local laboratory. Many of the new devices, such as lateral-flow (hand-held or dipstick) assays for using both nu- cleic acid and immunoassays, lead to complete independence from laboratory instrumentation. Novel variations on the original PCR assay include (among many) loop-mediated isothermal amplification, molecular beacons, multiplexed

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60 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE assays, twisted intercalating nucleic acid stabilizing molecules, and dA-tail cap- turing. Simultaneous interrogation of multiple sequences representing multiple bacterial and viral pathogens is provided by such systems as “lab-on-a-chip” designs and DNA-RNA microarrays; originally requiring laboratory access, these multiplex approaches have recently been adapted to lateral-flow platforms for field use. Nucleic acid-based and antibody-based platforms are most widespread, but direct chemical analysis of organisms with matrix-assisted laser desorption- ionization time of flight mass spectrometry is also possible. Identification is based on protein profiles of bacterial pathogens, viral glycoproteins, or even multiplexed PCR products. Microorganism-based biosensing methods—such as optical, surface plasmon resonance, amperometric, potentiometric, whole-cell, electrochemical, impedimetric, and piezoelectric methods—are being adapted from food-based assays to clinical use. Despite substantial advances in detection specificity and sensitivity, there is the remaining problem of sample concentration, as discussed above. Early stages of infectious diseases may have few organisms in accessible tissues. For exam- ple, early in Bacillus anthracis infection, few bacteria are in the bloodstream despite rapid replication because the bacteria are transported into the lymph nodes by dendritic cells (a subset of immune cells involved in early responses to infection) and are not accessible in traditional tissue sampling. By the time a suitable number of bacteria are present for diagnosis, the infection is rampant and usually fatal. Among the solutions to the problem are detection systems that have highly effective concentration methods that have been developed for such diseases as tuberculosis and malaria. Those systems (such as GeneXpert and DetermineTM TB-LAM) rely on automation of complex, time-consuming proce- dures and encase an entire process in sealed cartridges with excellent safety re- cords and reduce the time needed to confirm a diagnosis with high specificity and sensitivity. Finally, exponential increases in technology innovation are fueled by in- tense competition among companies and countries that have marked effects on research and development. Figure 3-4 shows the rates of performance improve- ment in two sets of technologies: recombinant DNA and synthetic biology (in- cluding rapid and low-cost DNA sequencing) (Aldrich et al., 2007). For exam- ple, revolutionary advances in DNA sequencing methods (next-generation, deep, and massively parallel sequencing) herald a time when tissue samples from in- fected animals can be subjected to genome sequencing even without the need for isolation of the organism. As of May 13, 2012, the complete DNA sequences of 11,681 prokaryotes and 3,097 viruses had been posted,11 and cost and time for sequencing are decreasing at an unprecedented rate; third-generation (single- molecule) sequencing will undoubtedly further revolutionize the field. 11 URL: http://www.ncbi.nlm.nih.gov/genome/browse/ (accessed May 12, 2012).

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AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 61 FIGURE 3-4 Rates of performance improvement of recombinant-DNA technology and synthetic biology. SOURCE: Aldrich et al. (2007). Reprinted with permission from Bio Economic Research Associates, LLC (bio-era™). All rights reserved. High biocontainment will be required in the near term for development, testing and validation of some of those approaches. Eventually, their application to plant and animal health will reduce, but not eliminate, the requirement for specialized laboratory space. 50-Year Lifespan of the Facility With forethought and proper planning, the design of a facility with a life- span of 50 years would take into account changes that might take place during the life of the building. They include changes in policy, research priorities, tech- nological developments, societal norms, and global interactions. For example, as noted above, technological advances will shorten the time to diagnosis and ex- pand the array of infections detectable with point-of-care or pen-side assays and reduce laboratory-based testing. Single catastrophic events, such as a massive outbreak or a terrorist event, can change the landscape of a research field and its associated policies. The decade after the 9/11 and 2001 anthrax attacks in the United States saw unprecedented changes in the regulatory and oversight environment for bio- medical research in the United States. The confluence of those two events had substantial effects on laboratory security and safety procedures that limited ac- cess to dangerous pathogens and altered research priorities. Similar increased awareness of security and safety issues has occurred on a global level. The new regulatory environment—on both the national and the international levels—is subject to constant adjustment and adaptation, and therefore would require that greater emphasis be placed on the harmonization of regulations: future national

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62 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE animal agricultural infrastructure and policies would need to be planned with the potential for these changes in mind. Similarly, societal values and public attitudes related to the welfare of agri- cultural animals continue to evolve (Blokhuis et al., 2008). Organizations such as OIE are actively promoting the importance of integrating animal health, ani- mal welfare, and food safety. Although the United States currently does not leg- islate food animal welfare,12 the European Commission recently adopted a new 4-year strategy (2012-2015) to improve the welfare of animals in the European Union.13 Research and development in animal protection will require BSL-3Ag and ABSL-4 for decades to come. Researchers will need to understand disease pathogenesis to develop efficient detection and diagnostic methods or new vac- cines. For example, some animals immunized with inactivated foot-and-mouth disease vaccines are still capable of maintaining persistent infection (Kitching, 2002). The variability of foot-and-mouth disease serotypes restricts the use of existing vaccine stocks in an outbreak until a full epidemiological characteriza- tion has been carried out and studies to determine whether the vaccine will pro- vide sufficient immunity against the viral outbreak strain have been conducted (Rodriguez and Gay, 2011). Furthermore, if vaccines are used to control an out- break, the ability to detect infection in vaccinated animals and to differentiate between infected and immunized animals is required if animal products are to be moved within the country and globally. As more is understood about disease progression and virulence determinants in infection, attenuated or recombinant viral vaccines will be produced by using reverse-engineering and other synthetic technologies, with serotype specificity and DIVA properties. Development of such a vaccine is well advanced in the United States and abroad. Those and other novel vaccine-production platforms are essential for rapid response to foot-and-mouth disease outbreaks and will need to be tested in large animals in strict containment. The committee notes that one such foot-and-mouth disease vaccine was licensed recently (June 2012). This vaccine was a product of PIADC and USDA-ARS research in cooperation with DHS and the private sector.14 Vaccine development for agents that are emerging as high-priority disease threats may also require high biocontainment. Bunyaviruses, such as Crimean- Congo hemorrhagic fever virus and Rift Valley fever virus, are the causative agents of devastating diseases and have an expanding host and geographic range. Investigation of those agents in livestock species is necessary. Recent advances in research methods such as infectious-virus rescue, novel electron microscopic techniques, and high-resolution structural analysis have been ap- 12 See URL: http://awic.nal.usda.gov/farm-animals/animal-welfare-audits-and-certifica tion-programs (accessed May 31, 2012). 13 See URL: http://ec.europa.eu/food/animal/welfare/actionplan/actionplan_en.htm. (accessed May 31, 2012). 14 See URL: http://www.prnewswire.com/news-releases/genvec-announces-conditiona l-approval-of-fmd-vaccine-for-cattle-157766595.html (accessed June 29, 2012).

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AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 63 plied to both emerging bunyaviruses and model species (Walter and Barr, 2011). The study of those agents has high priority in view of the lack of vaccines and therapeutics for their treatment and control and requires high biocontainment. Finally, the committee also recognizes that there are international research efforts to develop vaccination studies that involve no challenge infections of animals with live virus. These studies are critical for the large number of coun- tries recognized by the OIE as “foot-and-mouth disease-free with vaccination” whose foot-and-mouth disease research facilities are unable to use live FMDv for any studies or challenges. Efficacy studies for FMDv would be based solely on the evaluation of immune response elicited by vaccination, as is already hap- pening in the case of foot-and-mouth disease vaccines manufactured in South America under guidelines of the Pan-American Foot-and-Mouth Disease Center (PANAFTOSA). It is expected that efforts to develop alternative efficacy stud- ies of new vaccines without experimental challenge infections of live animals will continue to evolve given regulatory and societal pressures to limit the num- ber of animals used in infectious disease research, with an obvious impact on the capacity needed for animal studies in high biocontainment. SUMMARY Despite the marked expansion of high-biocontainment space in the United States since 2001, there remains no national ABSL-4 large-animal facility. Simi- larly, although BSL-3Ag containment space has expanded through construction of several new facilities (for example, the Biosecurity Research Institute and the National Animal Disease Center), the facilities at PIADC dedicated to FADs are dated and increasingly cost-inefficient. Thus, there is a critical national need for a dedicated facility that has modern BSL-3Ag and ABSL-4 large-animal capa- bilities. It would serve as the hub of the national strategy for the detection of and response to any incursion of an FAD. It would also be used for the study of in- fectious diseases of public-health importance in which livestock serve as key reservoir or amplifying hosts. US programs for detection of and response to FADs (those proposed to be located at the NBAF) would need to interface with similar activities and pro- grams of the National Biodefense Analysis and Countermeasures Center, the Centers for Disease Control and Prevention, the US Army Medical Research Institute for Infectious Diseases, USDA, NIH, and academic and state institu- tions to maximize efficiency and intellectual resources through interdisciplinary research that crosses traditional agency boundaries. Such interagency working relationships may have challenges, but would be essential for maximizing the use of the NBAF as well as other existing BSL-3Ag, BSL-4 and ABSL-4 labora- tories in the United States and the skilled workforce they employ. The rapidly evolving nature of disease threats confronting the animal industries of the United States and the technologies available to detect and respond to them de- mand a flexible and nimble strategy for programmatic and facility design. With

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64 CRITICAL LABORATORY NEEDS FOR ANIMAL AGRICULTURE that background, in Chapter 4 the committee considers in more detail the three options presented in its statement of task: constructing the NBAF as currently designed, scaling back the size and scope of the proposed NBAF, and maintain- ing the current PIADC and leveraging US capability and capacity through inter- national laboratories that have ABSL-4 large-animal space. REFERENCES Aldrich, S.C., J. Newcomb, and R. Carlson. 2007. Figure 1-2. An inflection point for biological technology . In Genome Synthesis and Design Futures: Implications for the US Economy. Bio-era.net [online]. Available: http://www.bio-era.net/reports/ genome.html (accessed June 5, 2012). Baker, M.G., and D.P. Fidler. 2006. Global public health surveillance under new interna- tional health regulations. Emerging Infectious Disease 12(7):1058-1065. Berns, K.I., A. Casadevall, M.L. Cohen, S. Ehrlich, L.W. Enquist, J.P. Fitch, D.R. Franz, C.M. Fraser-Liggett, C.M. Grant, M.J. Imperiale, J. Kanabrocki, P.S. Keim, S.M. Lemon, S.B. Levy, J.R. Lumpkin, J.F. Miller, R. Murch, M.E. Nance, M.T. Oster- holm, D.A. Relman, J.A. Roth, and A. Vidaver. 2012. Adaptations of avian flu virus are a cause for concern. Science 335(6069):660-661. Blokhuis, H.J., L.J. Keeling, A. Gavinelli, and J. Serratosa. 2008. Animal welfare’s im- pact on the food chain. Trends in Food Science and Technology 19 (suppl. 1):S79- S87. Brownlie, J., C. Peckham, J. Waage, M. Woolhouse, C. Lyall, L. Meagher, J. Tait, M. Bay- lis, and A. Nicoll. 2006. Foresight. Infectious Diseases: Preparing for the Future. Fu- ture Threats. London: Office of Science and Innovation [online]. Available: http://www.bis.gov.uk/assets/foresight/docs/infectious-diseases/t1.pdf (accessed June 4, 2012). CDC (Centers for Disease Control and Prevention). 2009. Biosafety in Microbiological and Biomedical Laboratories (BMBL), 5th Ed. (CDC) 21-1112. [online]. Available: http:// www.cdc.gov/biosafety/publications/bmbl5/BMBL.pdf (accessed June 5, 2012). CNA. 2011. Enhancing Ag Resiliency: The Agricultural Industry Perspective of Utilizing Agricultural Screening Tools. Report from the Agricultural Screening Tools Work- shop, April 2011, Washington D.C. College Station, TX: National Center for For- eign Animal and Zoonotic Disease Defense, Texas A&M University [online]. Avail- able; http://fazd.tamu.edu/files/2011/06/ASTII-Report-FINAL.pdf (accessed June 5, 2012). Enserink, M., and J. Cohen. 2012. One H5N1 paper finally goes to press; Second greenlighted. Science 336(6081):529-530. Fidler, D.P. 2005. From international sanitary conventions to global health security: The new international health regulations. Chinese Journal of International Law 4(2):325- 392. IOM (Institute of Medicine). 2003. Microbial Threats to Health: Emergence, Detection, and Response. M.S. Smolinski, M. A. Hamburg, and J. Lederberg, eds. Washington, DC: The National Academies Press. IOM and NRC (National Research Council). 2009. Sustaining Global Surveillance and Response to Emerging Zoonotic Diseases. G.T. Keusch, M. Pappaioanou, M.C. Gonzalez, K.A. Scott, and P. Tsai, eds. Washington, DC: The National Academies Press.

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AN INTEGRATED NATIONAL SYSTEM FOR ADDRESSING DISEASES 65 Kahn, C.M., and S. Line, eds. 2011. Akabane virus infection. The Merck Veterinary Manual. Whitehouse Station, NJ: Merck [online]. Available: http://www.merck vetmanual.com/mvm/index.jsp?cfile=htm/bc/50804.htm (accessed June 29, 2012). Kitching, R.P. 2002. Identification of foot and mouth disease virus carrier and subclini- cally infected animals and differentiation from vaccinated animals. Scientific and Technical Review 21(3):531-538. NAS (National Academy of Sciences) and NRC. 2012. Biosecurity Challenges of the Global Expansion of High-Containment Biological Laboratories: Summary of a Workshop. Washington, DC: The National Academies Press. NASDARF (The National Association of State Departments of Agriculture Research Foundation). 2001. The Animal Health Safeguarding Review: Results and Recom- mendations, October 2001 [online]. Available: http://www.aphis.usda.gov/vs/pdf_ files/safeguarding.pdf (accessed June 8, 2012). NRC (National Research Council). 2003. Countering Agricultural Bioterrorism. Wash- ington, DC: The National Academies Press. OIE (World Organization for Animal Health). 2010. Chapter 1.2 Criteria for Listing Dis- eases Article 1.2.1. Terrestrial Animal Health Code 2010 [online]. Available: http://web.oie.int/eng/normes/mcode/en_chapitre_1.1.2.pdf (accessed June 1, 2012). Rodriguez, L.L., and C.G. Gay. 2011. Development of vaccines toward the global control and eradication of foot-and-mouth disease. Expert Review of Vaccines 10(3):377- 387. USDA (US Department of Agriculture). 2012. USDA Responses and Supporting Materi- als to the Questions Sent by the Committee. April 27, 2012. USDA-APHIS (US Department of Agriculture, Animal and Plant Health Inspection Ser- vice). 2012. National Animal Health Laboratory Network (NAHLN) [online]. Available: http://www.aphis.usda.gov/animal_health/nahln/content/wp_c_map_disp. php?lab=all_labs_disease_designations (accessed June 5, 2012). Walter, C.T., and J.N. Barr. 2011. Recent advances in the molecular and cellular biology of bunyaviruses. Journal of General Virology 92:2467-2484. WHO (World Health Organization). 2007. International Health Regulations (2005): Ar- eas of Work for Implementation. WHO/CDS/EPR/IHR/2007.1. France, Lyon: World Health Organization [online]. Available: http://www.who.int/ihr/finalversion 9Nov07.pdf (accessed June 4, 2012).

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